Autism spectrum disorder is a major public health problem affecting children and adults, with the number of cases having tripled in the US in the past 15 years, and with an incidence of 67 in 10,000 people. Autism is a lifelong debilitating developmental brain disorder characterized by impairments in social interaction and verbal/non-verbal communication. In a study of adolescents and young adults with autism using MRI diffusion tensor tracking (DTT), we previously observed unique diffusion changes indicating a slowing of microscopic water movements (diffusion) across nerve fibers within white matter pathways used for recognizing faces and face emotions (critical aspects of social interaction and non-verbal communication). Because these functions are often affected in young children as well as adults with autism, and such unique diffusion changes are usually not seen in acquired or adult-onset disorders, we interpreted these DTT findings to indicate a primary, early-developmental change. The unusual slowing of diffusion was particularly associated with a lower ability of the autism participants to recognize faces. This relation suggests that the pathway is microscopically composed of small-diameter nerve fibers (axons), which would have a slower neural conduction speed and lower function. To determine whether such changes are a fundamental, primary abnormality in autism that occurs early in infant development, we will use DTT and diffusion-sensitive methods to: 1) test for these water diffusion changes in the same face processing pathways in infants at high-risk for autism (compared to low-risk infants);and 2) test for similar changes in language pathways in high-risk versus low-risk infants. We plan to study 20 high-risk infants and 20 individually-matched low-risk infants, where risk is assigned based on existence of a sibling with autism. The functional significance of DTT results will be determined by comparison to relevant face-processing and language tests designed for infants. The results will determine if the abnormalities seen in face-processing pathways in adolescents and young adults are more severe, similar, or less severe in infants;whether this diffusion pattern extends to other pathways potentially related to the core features of autism;and if infants exhibit non-specific diffusion changes in other pathways seen in young adults with autism that appear to be secondary in nature. Our long-term goals are to: 1) provide a better understanding of the underlying biological mechanisms and causes of autism;2) improve the early diagnosis, screening, risk assessment, subtype characterization, and design/planning of early treatments and interventions;and 3) provide safe, non-invasive measures (biomarkers) of very early brain changes in autism that can be used during infancy and childhood to determine relationships between genetic/immunological/environmental events (e.g., immunization) and the onset of measurable microscopic brain changes. PUBLIC HEALTH RELEVANCE: In a study of young adults with autism using MRI diffusion tensor tracking (DTT), we previously observed changes suggesting small-diameter nerve fibers in the white matter pathways involved in the recognition of faces and facial emotions (critical aspects of social interaction and non-verbal communication often affected in autism). To determine whether such changes are a fundamental abnormality that occurs early in infant development, we will use DTT and new diffusion-sensitive MRI methods to: 1) test for these pathway changes in infants at high-risk for autism compared to infants at low risk (where risk is based on the existence of an affected sibling), and 2) test for similar changes in language pathways in high-risk versus low-risk infants. Our long-term goal is to 1) provide a better understanding of the biological causes of autism, 2) improve the early diagnosis, screening, and treatment of autism, and 3) provide measures (biomarkers) of very early brain changes in autism that can be used to study the time relation between genetic, immunological, and environmental events (e.g., immunization) and the onset of measurable brain changes.